Berberine, a natural molecular glue degrader, overcomes CML resistance via TRIM28-mediated HIF1α ubiquitination and subsequent ferroptosis.

BCR-ABL1-independent resistance remains a major challenge in chronic myeloid leukemia (CML). These resistant cells exhibit elevated basal reactive oxygen species (ROS), which creates a therapeutic vulnerability. We show that berberine (BBR) acts as a natural molecular glue degrader of Hypoxia-Inducible Factor 1 Alpha (HIF1α) to exploit this vulnerability. BBR directly binds HIF1α at E816, stabilizing its interaction with the E3 ubiquitin ligase TRIM28, which subsequently promotes K48-linked ubiquitination of HIF1α. HIF1α degradation transcriptionally suppresses PDE4D, leading to cyclic AMP (cAMP) accumulation and activation of the xCT axis, depleting glutathione. BBR also induces metallothionein-mediated metal ion dyshomeostasis by upregulating MT1X, MT2A, and SLC30A8 mRNA levels, sequestering Cu2+/Zn2+ and inhibiting SOD1. These effects synergistically upregulate ROS to trigger ferroptosis, overcoming BCR-ABL1-independent resistance in vivo and in vitro. Thus, our findings identify an oxidative stress vulnerability in BCR-ABL1-independent resistant cells and show that BBR, a natural molecular glue degrader, exploits this vulnerability through HIF1α ubiquitination and degradation. This leads to elevated ROS that subsequently triggers ferroptosis, thereby offering a new therapeutic strategy against BCR-ABL1-independent resistance.